PROJECT SUMMARY/ABSTRACT This application addresses Broad Challenge area (04) Clinical research and Specific Challenge topic, (AI-102) the human immune response to infection and immunization-profiling via modern immunological and systems biology. Malaria remains a major source of morbidity and mortality in many countries. Fundamental questions such as the mechanisms of immunity, the role of the immune system in cerebral disease and the mechanism of loss of malaria immunity in HIV infected adults remain poorly understood. The clinical relevance of these issues is extremely high. Patients that develop cerebral malaria have a 15% mortality rate despite potent antimalarials. HIV has resulted in hundreds of thousands of additional symptomatic infections in adults who previously were immune. Understanding mechanisms of cerebral malaria and protection mediated by the immune system will guide interventions to improve survival rates and lessen HIV related malaria. The lack of understanding of the immune systems role in these clinical scenarios is in part due to a lack of comprehensive analysis of the immune response in natural cohorts. We propose to carry out immune profiling through new methods of whole genome transcription in malaria infected patients to provide an unbiased view of immune response in malaria infection. This analysis will be carried out in two phenotypically highly characterized cohorts 1) children with cerebral malaria 2) adults with HIV/malaria co-infection. There is prior evidence to suggest that a deregulated, pro-inflammatory immune response is the mechanism that gives rise to cerebral malaria. Specific Aim I will address this hypothesis through whole genome transcriptional profiling in a cerebral malaria disease cohort. Through an ongoing study of cerebral malaria, peripheral blood aliquots are available to analyze host transcriptional responses. Comparison of whole genome transcriptional responses to other datasets including mild malaria and systemic inflammatory syndrome will be carried out. We will develop a prediction model for survivors vs. non survivors of cerebral malaria with the goal of developing biomarkers that can be used in patient care. Our second specific aim is based on the clinical observation that HIV infected adults lose their natural immunity to malaria disease. Typically immune adults are frequently infected but have no physical symptoms or laboratory abnormalities. HIV infected patients have an increase in the risk of asymptomatic parasitemia, symptomatic malaria and more severe disease;this increase is inversely proportional to CD4+ T cell count. The basis of this loss of immunity is unknown. Through the analysis of a second cohort, we will characterize the immune response to malaria in HIV negative and HIV positive adults. Using biostatistical and computational analysis we will identify the genes and biological pathways that have altered expression based on CD4+T cell counts. These studies may provide insight into components of protective immunity in malaria. Conversely we will further understand how HIV impacts patients'immune response to malaria which may inform studies of HIV and other pathogens. All datasets will be compared to previously published relevant transcriptional host response profiling using systems biology and computational biology approaches to develop broader models of immune response to pathogens. This study brings together two components that are critical for high impact, high quality clinical research. The first is the clinical expertise in the disease and the experience and cohorts to carry out high quality field research in malaria and HIV. The second is the experience and creativity of the analysis team which include epidemiologists, biostatisticians and computational biologists. This proposal has brought together an outstanding team with these skills to provide high impact results to inform pathogenesis models and vaccine/drug development in malaria.